Identification and Structure-Activity Relationship Study of Imidazo[1,2-a]pyridine-3-amines as First Selective Inhibitors of Excitatory Amino Acid Transporter Subtype 3 (EAAT3)

Peng Wu; Walden E Bjørn-Yoshimoto; Markus Staudt; Anders A Jensen; Lennart Bunch

doi:10.1021/acschemneuro.9b00447

Identification and Structure-Activity Relationship Study of Imidazo[1,2-a]pyridine-3-amines as First Selective Inhibitors of Excitatory Amino Acid Transporter Subtype 3 (EAAT3)

Peng Wu, Walden E Bjørn-Yoshimoto, Markus Staudt, Anders A Jensen, Lennart Bunch

3 Citations (Scopus)

Abstract

In the present study, screening of a library of 49,087 compounds at the excitatory amino acid transporter subtype 3 (EAAT3) led to the identification of 2-(furan-2-yl)-8-methyl-N-(o-tolyl)imidazo[1,2-a]pyridin-3-amine (3a) which showed a >20-fold preference for inhibition of EAAT3 (IC50 = 13 μM) over EAAT1,2,4 (EAAT1: IC50 ∼ 250 μM; EAAT2,4: IC50 > 250 μM). It was shown that a small lipophilic substituent (methyl or bromine) at the 7- and/or 8-position was essential for activity. Furthermore, the substitution pattern of the o-tolyl group (compound 5b) and the chemical nature of the substituent in the 2-position (compound 7b) were shown to be essential for the selectivity toward EAAT3 over EAAT1,2. The most prominent analogues to come out of this study are 3a and 3e that display ∼35-fold selectivity for EAAT3 (IC50 = 7.2 μM) over EAAT1,2,4 (IC50 ∼ 250 μM).

Original language	English
Journal	ACS Chemical Neuroscience
Volume	10
Pages (from-to)	4414-4429
ISSN	1948-7193
DOIs	https://doi.org/10.1021/acschemneuro.9b00447
Publication status	Published - 16 Oct 2019

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Identification and Structure-Activity Relationship Study of Imidazo[1,2-a]pyridine-3-amines as First Selective Inhibitors of Excitatory Amino Acid Transporter Subtype 3 (EAAT3). / Wu, Peng; Bjørn-Yoshimoto, Walden E ; Staudt, Markus et al.
In: ACS Chemical Neuroscience, Vol. 10, 16.10.2019, p. 4414-4429.

Research output: Contribution to journal › Journal article › Research › peer-review

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title = "Identification and Structure-Activity Relationship Study of Imidazo[1,2-a]pyridine-3-amines as First Selective Inhibitors of Excitatory Amino Acid Transporter Subtype 3 (EAAT3)",

abstract = "In the present study, screening of a library of 49,087 compounds at the excitatory amino acid transporter subtype 3 (EAAT3) led to the identification of 2-(furan-2-yl)-8-methyl-N-(o-tolyl)imidazo[1,2-a]pyridin-3-amine (3a) which showed a >20-fold preference for inhibition of EAAT3 (IC50 = 13 μM) over EAAT1,2,4 (EAAT1: IC50 ∼ 250 μM; EAAT2,4: IC50 > 250 μM). It was shown that a small lipophilic substituent (methyl or bromine) at the 7- and/or 8-position was essential for activity. Furthermore, the substitution pattern of the o-tolyl group (compound 5b) and the chemical nature of the substituent in the 2-position (compound 7b) were shown to be essential for the selectivity toward EAAT3 over EAAT1,2. The most prominent analogues to come out of this study are 3a and 3e that display ∼35-fold selectivity for EAAT3 (IC50 = 7.2 μM) over EAAT1,2,4 (IC50 ∼ 250 μM).",

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AU - Wu, Peng

AU - Bjørn-Yoshimoto, Walden E

AU - Staudt, Markus

AU - Jensen, Anders A

AU - Bunch, Lennart

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N2 - In the present study, screening of a library of 49,087 compounds at the excitatory amino acid transporter subtype 3 (EAAT3) led to the identification of 2-(furan-2-yl)-8-methyl-N-(o-tolyl)imidazo[1,2-a]pyridin-3-amine (3a) which showed a >20-fold preference for inhibition of EAAT3 (IC50 = 13 μM) over EAAT1,2,4 (EAAT1: IC50 ∼ 250 μM; EAAT2,4: IC50 > 250 μM). It was shown that a small lipophilic substituent (methyl or bromine) at the 7- and/or 8-position was essential for activity. Furthermore, the substitution pattern of the o-tolyl group (compound 5b) and the chemical nature of the substituent in the 2-position (compound 7b) were shown to be essential for the selectivity toward EAAT3 over EAAT1,2. The most prominent analogues to come out of this study are 3a and 3e that display ∼35-fold selectivity for EAAT3 (IC50 = 7.2 μM) over EAAT1,2,4 (IC50 ∼ 250 μM).

AB - In the present study, screening of a library of 49,087 compounds at the excitatory amino acid transporter subtype 3 (EAAT3) led to the identification of 2-(furan-2-yl)-8-methyl-N-(o-tolyl)imidazo[1,2-a]pyridin-3-amine (3a) which showed a >20-fold preference for inhibition of EAAT3 (IC50 = 13 μM) over EAAT1,2,4 (EAAT1: IC50 ∼ 250 μM; EAAT2,4: IC50 > 250 μM). It was shown that a small lipophilic substituent (methyl or bromine) at the 7- and/or 8-position was essential for activity. Furthermore, the substitution pattern of the o-tolyl group (compound 5b) and the chemical nature of the substituent in the 2-position (compound 7b) were shown to be essential for the selectivity toward EAAT3 over EAAT1,2. The most prominent analogues to come out of this study are 3a and 3e that display ∼35-fold selectivity for EAAT3 (IC50 = 7.2 μM) over EAAT1,2,4 (IC50 ∼ 250 μM).

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DO - 10.1021/acschemneuro.9b00447

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ER -

Identification and Structure-Activity Relationship Study of Imidazo[1,2-a]pyridine-3-amines as First Selective Inhibitors of Excitatory Amino Acid Transporter Subtype 3 (EAAT3)

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